Dabrafenib + trametinib (dab + tram) in relapsed/refractory (r/r) <i>BRAF</i> V600–mutant pediatric high-grade glioma (pHGG): Primary analysis of a phase II trial.
Authors: Darren R. Hargrave, Keita Terashima, Junichi Hara, Uwe R. Kordes, Santhosh A. Upadhyaya, Felix Sahm, Eric Bouffet, Roger J. Packer, Olaf Witt, Lali Sandalic, Agnieszka Kieloch, Mark W. Russo, Kenneth J. Cohen
Journal: Journal of Clinical Oncology (2022)

2009 Background: HGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. Overall response rates (ORRs) with current standards of care are low, particularly in the second line, and 2-y overall survival (OS) rates are ≤35%. BRAF V600 mutation is infrequent (≈5% of pHGGs) but associated with improved survival from time of initial diagnosis. In previous trials, dab monotherapy and dab + tram yielded encouraging outcomes in BRAF V600–mutant HGG in pediatric and adult patients (pts), respectively. We describe the results of a Phase II study (NCT02684058) of dab + tram in r/r BRAF V600–mutant pHGG. Methods: Pts aged 1 to &lt;18 y with BRAF V600–mutant HGGs and Karnofsky/Lansky performance status ≥50% who had failed first-line therapy were enrolled in a single-arm cohort. Pts received dab twice daily (&lt;12 y, 5.25 mg/kg/d; ≥12 y, 4.5 mg/kg/d) + tram once daily (&lt;6 y, 0.032 mg/kg/d; ≥6 y, 0.025 mg/kg/d). The primary endpoint was ORR (independent review; HGG-RANO criteria); secondary endpoints included ORR (investigator review), duration of response (DOR), progression-free survival (PFS), OS, and safety. Results: A total of 41 pts with diverse WHO Grade III/IV gliomas were enrolled; median time since diagnosis was 17.4 mo (range, 2.7-174.3 mo), and most had prior surgery (97.6%), radiotherapy (90.2%), and/or systemic antineoplastic therapy (80.5%). At data cutoff (August 23, 2021; median follow-up, 25.1 mo), 21 pts (51.2%) remained on treatment; most discontinuations (16 of 20) were due to progressive disease. Median exposure was 72.7 wk (range, 1.3-172.1 wk). The primary endpoint was met, with an independently assessed ORR of 56.1% (95% CI, 39.7%-71.5%). Median DOR was 22.2 mo (95% CI, 7.6 mo-not estimable [NE]; 12-mo Kaplan-Meier [KM] DOR rate, 62.2%), and median PFS was 9.0 mo (95% CI, 5.3-24.0 mo; 12-mo KM PFS rate, 44.1%). There were 14 deaths (34.1%), with 12 due to HGG and 2 due to serious adverse events (AEs; encephalomyelitis and intracranial pressure increased [n = 1 each], not treatment related per investigators); median OS was 32.8 mo (95% CI, 19.2 mo-NE; 12-mo KM OS rate, 76.3%). The most common all-cause AEs were pyrexia (51.2%), headache (34.1%), dry skin (31.7%), vomiting (29.3%), and diarrhea (24.4%). Two pts (4.9%) had AEs leading to discontinuation (both rash), and 26 (63.4%) had AEs leading to dose modification. Conclusions: Treatment with dab + tram demonstrated an improvement in ORR, response durability, and survival compared with estimates based on historical observations with current treatment approaches in r/r BRAF V600–mutant pHGG. Safety was consistent with the established profile of dab + tram in other indications. Thus, dab + tram may represent a critical treatment advance for this pt population with high unmet need. Clinical trial information: NCT02684058.